Low Salt Forms of Polyallylamine

ABSTRACT

Disclosed is a pharmaceutical composition comprising a stable polyallylamine hydrochloride polymer in which between about 4% to about 12% by weight of the polymer is a chloride anion and a pharmaceutically acceptable carrier or diluent.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/284,445, filed on Apr. 18, 2001.

The entire teachings of the above application are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Polyallylamine polymers have found many uses in recent years astherapeutic agents. For example, polyallylamines have been reported tobe effective in treating patients with elevated serum phosphate levelsand hyperphosphatemia (e.g., U.S. Pat. Nos. 5,496,545 and 5,667,775).Elevated serum phosphate is often present in patients with renalinsufficiency, hypoparathyroidism, acute untreated acromegaly andovermedication with therapeutics comprising phosphate salts.Polyallylamines have also found uses as bile acid sequestrants (e.g.,U.S. Pat. Nos. 5,624,963, 5,703,188, 5,840,766 and 6,060,517) and forlowering uric acid levels (U.S. Pat. No. 5,985,938). Of particular noteis the drug Sevelamer Hydrochloride (Sevelamer), which has been approvedby the Food and Drug Administration to treat hyperphosphatemia.

The characteristic structural feature of a polyallylamine polymer is thepresence of repeat units from polymerized allylamine monomer. Forexample, Sevelamer is a homopolymer comprising repeat units in which theamine nitrogen from the polymerized allylamine monomer is unsubstituted.The structure of the repeat unit from the Sevelamer homopolymer is shownbelow in Structural Formula (I):

In other polyallylamines, the amine nitrogen in the polymerized allylmonomer repeat units is substituted. Suitable substituents are describedbelow.

To maintain potency and prevent undesired side effects, it is criticallyimportant that the ingredients in a pharmaceutical product, includingthe pharmacologically active ingredient, are chemically stable overextended time periods, typically for at least two years. During thistime, decomposition rates must be within acceptable limits. However,amine compounds are susceptible to oxidative decomposition. For thisreason, drugs containing amine functional groups are generally storedand administered in the form of a salt, typically a hydrochloride (HCl)salt, which, in most cases, is more stable than the corresponding freeamine. Sevelamer, for example, is stored and administered as a salt inwhich about 40% of the amine groups are protonated as the hydrochloridesalt (about 18% by weight of the polymer is chloride).

SUMMARY OF THE INVENTION

Surprisingly, it has now been found that amine-containing polymers inwhich significantly less than 40% of the amine group are protonateddecompose at rates that are within acceptable limits for drug stabilitypurposes. The art has established guidelines for drug stability testingwhich include: International Conference on Harmonization (ICH), SectionQ1A “Stability Testing of New Drug Substances and Products” (Revised)and; the Code of Federal Regulations (CFR), 21 CFR 211.166 “Guidelinefor Submitting Documentation for the Stability of Human Drugs andBiologics”. For example, it has been shown that under acceleratedstability testing conditions, polyallylamine hydrochloride with betweenabout 4.0% by weight of chloride to about 12% by weight of chloride canbe stored for at least two years with minimal decomposition. Inaddition, this “low chloride” or “low salt” form of polyallylaminehydrochloride possesses the same desirable therapeutic and formulationproperties as do the corresponding polymers with higher levels ofchloride. Based on the foregoing discoveries, stable pharmaceuticalformulations of polyallylamine polymers with low levels of protonationand novel pharmaceutical compositions comprising said polymers aredisclosed herein. As used herein, the term “stable” with reference tothe polymer and its pharmaceutical formulation means that thepharmaceutical formulation of the polymer decomposes at rates that arewithin acceptable limits for drug stability purposes, while maintainingtherapeutic effectiveness.

One embodiment of the present invention is a stable, polyallylaminepolymer wherein about 9.0% to about 27.0% of the amine groups in thepolyallylamine polymer are protonated (e.g., polyallylaminehydrochloride with between about 4.0% by weight and about 12.0% byweight of the polymer is chloride anion). More preferably, between about11% to about 20.0% of the amine groups in the polyallylamine polymer areprotonated (e.g., polyallylamine hydrochloride with between about 5.0%by weight and about 9.0% by weight of the polymer is chloride anion).The amine groups are preferably protonated with as a hydrochloride salt.

Another embodiment of the present invention is a pharmaceuticalcomposition comprising the stable polyallylamine polymer described aboveand a pharmaceutically acceptable carrier or diluent.

The low salt form of polyallylamine has important therapeutic and drugformulation advantages compared with the corresponding polymer havinghigher levels of salt. For example, polyallylamines are commonly used toreduce phosphate serum levels in patients with renal failure.Unfortunately, most patients with renal failure also suffer from lowblood pH or “acidosis”. Low salt forms of polyallylamine have lessanions to release into the blood and possess an increase in the numberof unprotonated, basic amines compared with higher salt forms of thepolymer, and thereby would tend to increase blood pH. Secondly, low saltcontent decreases the weight and bulk of the ultimate dosage form,thereby making it easier to formulate and administer,

DETAILED DESCRIPTION OF THE INVENTION

A polyallylamine is a polymer having repeat units from polymerized allylamine monomer(s). The amine group of an allyl monomer can beunsubstituted or substituted with, for example, one or two a C₁-C₁₀straight chain or branched alkyl groups. The alkyl group(s) isoptionally substituted with one or more hydroxyl, amine, halo, phenyl,amide or nitrile groups. Preferably, the polyallylamine polymers of thepresent invention comprise repeat units represented by StructuralFormula (I):

A polyallylamine can be a copolymer comprising repeat units from two ormore different polymerized allyl monomers or with repeat units frompolymerized allyl monomer(s) and repeat units from polymerized non-allylmonomer(s). Examples of suitable non-allyl monomers include acrylamidemonomers, acrylate monomer, maleic acid, malimide monomers, vinylacylate monomers and alkyl substituted olefines. Preferably, however,the polyallylamines of the present invention comprise repeat unitssolely from polymerized allyl amine monomer. More preferably, thepolyallylamine polymers of the present invention are homopolymers. Evenmore preferably, the polyallylamine polymers of the present inventionare homopolymers of repeat units represented by Structural Formula (I).

Although a polyallylamine can be uncrosslinked, it is preferablycrosslinked. Suitable crosslinking agents include epichlorohydrin, 1,4butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether,1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane,1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluenediisocyanate, acryloyl chloride, and pyromellitic dianhydride.Epichlorohydrin is a preferred crosslinking agent. Typically, betweenabout 9% and about 30% of the allylic nitrogen atoms are bonded to acrosslinking group, preferably between 15% and about 21%. Preferably,epichlorohydrin is the crosslinking agent, resulting in 2-hydroxypropylcrosslinking groups.

Polyallylamines can be protonated with organic or inorganic acidscomprising physiologically acceptable anions. The anions can bepartially or completely replaced with other physiologically acceptableanions by various means, including by passing the polymer over an anionexchange resin prior to crosslinking. A polyallyamine polymer cancomprise more than one type of anion. Examples of suitable inorganicanions include halide (especially chloride), carbonate, bicarbonate,sulfate, bisulfate, hydroxide, nitrate, persulfate and sulfite. Suitableorganic ions include acetate, ascorbate, benzoate, citrate, dihydrogencitrate, hydrogen citrate, oxalate, succinate, tartrate, taurocholate,glycocholate, and cholate. Chloride is a preferred anion.

In a preferred embodiment, the polyallylamine polymer is crosslinkedwith epichlorohydrin and between about 9% to about'30% (preferably about15% to about 21%) of the allylic nitrogen atoms are bonded to acrosslinking group and the anion is chloride. More preferably, thepolyallylamine polymer is a homopolymer. Even more preferably, thepolyallylamine polymer is a homopolymer comprising repeat unitsrepresented by Structural Formula (I).

In a most preferred embodiment, the polyallylamine polymer ishomopolyallyamine crosslinked with about 9.0-9.8% epichlorohydrin,preferably 9.3-9.5%, and is the active chemical component of the drugknown as Sevelamer HCl.

The polyallylamine polymers described'herein are useful for treating avariety of conditions, including hyperphosphatemia (e.g., patients withhigh serum phosphate levels such as patients with end stage renaldisease, hypoparathyroidism, acromegaly, and overmedication withphosphate salts). The polymers described herein are also suitable asbile acid sequestrants, in the treatment of Wilson's Disease, forlowering uric acid levels in a patient, and in the prevention ofthrombosis of shunts such as those that may be used in conjunction withrenal dialysis. Dosages of between about 0.5 gram/day and about 10grams/day are typical, and preferably between about 3 grams/day andabout 6 grams/day.

The polymer can be administered alone or in a pharmaceutical compositioncomprising the polymer, a pharmaceutically acceptable carrier ordiluent, and optionally, one or more additional drugs. The polymers arepreferably administered orally and even more preferably administeredorally with a meal. Suitable carriers and diluents will be immediatelyapparent to persons skilled in the art. These carrier and diluentmaterials, either inorganic or organic in nature, include, for example,silicon oxide, stearic acid, gelatin, albumin, lactose, starch,magnesium stearate preservatives (stabilizers), melting agents,emulsifying agents, salts and buffers. The therapeutically effectiveamount can be administered in a series of doses separated by appropriatetime intervals such as minutes or hours.

Further descriptions of suitable dosages, dosages forms and routes ofadministration are provided in U.S. Pat. Nos. 5,496,545, 5,667,7756,083,495, 5,702,696 and 5,487,999. The entire teachings of thesepatents are incorporated herein by reference.

The invention is illustrated by the following examples which are notintended to be limiting in any way.

EXAMPLES Example 1 Preparation of Low Chloride Sevelamer Hydrochloride(Polyallylamine Homopolymer)

Sevelamer HCl of various chloride levels (˜1%, ˜5%, ˜9% by weight) wasprepared from commercial bulk Sevelamer (˜18% chloride by weight)manufactured by Dow Chemicals (Midland, Mich.). The bulk Sevelamer wasslurried in water, and further neutralized with 50% aqueous sodiumhydroxide (NaOH) solution. Varying amounts of NaOH were added to achievethe desired reduction in the level of chloride by weight of the polymer.For example, 0.5 equivalents of NaOH added with respect to the totalchloride in Renagel (˜18%), yields approximately 50% reduction inchloride resulting in Sevelamer having about 9% chloride by weight ofthe polymer, 0.75 equivalents of NaOH yields approximately a 75%reduction in chloride resulting in Sevelamer having about 5% chloride byweight, and 0.95 equivalents or higher resulted in Sevelamer havingabout 1% chloride by weight.

Neutralized Sevelamer was filtered and resuspended in an adequate amountof water such that conductive slurry is less than 1 mS/cm. Thesuspension was filtered and placed dried in a 70° C. forced air ovenuntil it was dried. The dried Sevelamer was then ground and sieved.

Alternatively, polyallylamine polymers crosslinked with epichlorohydrinmay be synthesized as described in U.S. Pat. Nos. 5,496,545, 5,667,7756,083,495, 5,702,696 and 5,487,999, and neutralized as described aboveto yield the desired percentage of chloride by weight of the polymer.

Example 2 Stability Studies with Low Chloride Sevelamer HCl

The low chloride Sevelamer Hydrochloride polymers (a polyallylaminehomopolymer) described in Example 1 having approximately 9%, 5%, and 1%chloride by weight of the polymer respectively, were tested forstability in accordance with the guidelines of the InternationalConference on Harmonization (ICH). The accelerated stability testsincluded placing each of the respective low chloride polymer samples, inan oven at 40 C with 75% relative humidity for 1, 2, 3 and 6 months. Ateach time point, a portion of each respective polymer sample was removedand analyzed using two assays, the phosphate binding assay and thesoluble oligomers assay. Both assays are demonstrated as stabilityindicating assays for polyallylamine polymers.

The phosphate binding assay determines the phosphate binding capacity ofSevelamer Hydrochloride, which is an indicator of its therapeuticeffectiveness. The assay is performed by mixing the SevelamerHydrochloride samples with a solution of known phosphate concentration,filtering off the polymer-phosphate complex and quantitating the unboundphosphate concentration by ion chromatography.

The soluble oligomers assay determines the amount of soluble oligomersin each Sevelamer Hydrochloride sample. Titratable amine and solubleoligomer content are indicative of polymer stability at each time point.The assay is performed by reacting ninhydrin with oligomers that havebeen extracted from samples of Sevelamer Hydrochloride at eachrespective time point. Spectrophotometric quantitation to determine theamount of residual soluble oligomers was performed by comparing theabsorbance of the derivatized sample extract to the absorbance of knownstandards.

The results of the stability testing demonstrate that the 9% and 5%chloride composition by weight samples, have very good stabilityprofiles (meaning they retain the ability to bind phosphate and theresidual soluble oligomer levels are within acceptable limits for eachsample). The results of this study indicate that low chloride versionsof Sevelamer Hydrochloride with 9% and 5% chloride composition by weightrespectively, have stability profiles that are similar to SevelamerHydrochloride having approximately 18% chloride content (the chloridecontent found in the currently marketed Sevelamer drug product). Theaccelerated stability results further indicate that the shelf life of alow chloride Sevelamer Hydrochloride drug product is the equivalent ofat least 2 years.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1-7. (canceled)
 8. A method of treating hyperphosphatemia in a patientin need thereof comprising administering to said patient apharmaceutical composition comprising a pharmaceutically acceptablecarrier or diluent and a stable polyallylamine hydrochloride polymerwherein between about 4% to about 12% by weight of the polymer ischloride anion and between about 9.0% to about 27.0% of the amine groupsin the polyallylamine polymer are protonated.
 9. The method of claim 8,wherein between about 5% to about 9% by weight of the polymer ischloride anion.
 10. The method of claim 9, wherein the polymer is ahomopolymer.
 11. The method of claim 10, wherein the polyallylaminehydrochloride polymer comprises a repeat unit represented by StructuralFormula (I):


12. The method of claim 11, wherein the polymer is crosslinked.
 13. Themethod of claim 12, wherein the polymer is crosslinked with2-hydroxypropyl crosslinking groups.
 14. The method of claim 8, whereinsaid pharmaceutical composition is administered in a dosage of betweenabout 0.5 grams/day to about 10 grams/day.
 15. The method of claim 14,wherein said pharmaceutical composition is administered in a dosage ofbetween about 0.5 grams/day to about 10 grams/day.
 16. A method oftreating hyperphosphatemia in a patient in need thereof comprisingadministering to said patient a pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and a stablepolyallylamine homopolymer comprising repeat units represented byStructural Formula (I):

wherein the homopolymer is crosslinked with 2-hydroxypropyl groups,between about 9% and about 30% of the amine groups in the homopolymerare bonded to one of the 2-hydroxypropyl crosslinking groups, andbetween about 5% and about 9% by weight of the homopolymer is chlorideanion and between about 9.0% to about 27.0% of the amine groups in thepolyallylamine polymer are protonated.
 17. The method of claim 16,wherein said pharmaceutical composition is administered in a dosage ofbetween about 0.5 grams/day to about 10 grams/day.